The application claims the benefit of U.K. patent application No. 9923314.0, filed Oct. 1, 1999.
The present invention is concerned with the acylation of indoles, specifically the preparation of 3-acylated indoles which may be further treated to provide indoles having an alternative substituent at the 3-position.
To date, the 3-acylation of indoles has typically been carried out by the method described, for example, in International Patent Application PCT/US91/07194, that is, by reacting a magnesium salt of the indole with an acid chloride: 
wherein Z is halogen and R is, for example, substituted pyrrolidinyl, azetidinyl, or piperidinyl.
The magnesium salt is prepared by reacting the appropriate indole with an alkyl or aryl magnesium halide, preferably ethyl magnesium bromide, in an inert solvent, for example, diethyl ether or tetrahydrofuran, at a temperature between xe2x88x9230xc2x0 C. and 65xc2x0 C., preferably about 25xc2x0 C.
The acid chloride is prepared by reacting the corresponding acid with, for example, oxalyl or thionyl chloride, in an inert solvent, for example, methylene chloride, diethyl ether or tetrahydrofuran, at a temperature between xe2x88x9210xc2x0 C. and 25xc2x0 C. Acids having an N-containing heterocyclic moiety may protect same from the resulting acid chloride by N-substitution with a suitable protecting group, for example, carboxybenzyl (CBZ).
A solution of the acid chloride is then added slowly to a stirred solution of the magnesium salt at a temperature between xe2x88x9230xc2x0 C. and 50xc2x0 C., preferably about 25xc2x0 C., to give the desired 3-acylated indole.
This process for the preparation of 3-acylated indoles, requiring as it does the independent preparation of each starting material, is both time- and labour-intensive and does not lend itself readily to commercial scale-up.
We have therefore developed a new methodology for the preparation of 3-acylated indoles which eliminates the need for independent preparation of the aforementioned starting materials. According to the present invention, 3-acylated indoles may be obtained in good yield by adding solutions of the acid chloride (N-protected if necessary) and the alkyl or aryl magnesium halide separately and simultaneously to a solution of the indole at xe2x80x98synchronisedxe2x80x99 rates of molar addition.
Thus the problem addressed by the present invention is to provide a quick and cost effective method for preparing 3-acylated indoles which avoids the unsatisfactory convergent synthesis of the prior art, particularly the necessity to prepare and isolate the magnesium salt of the indole.
As a further cost-saving measure, the process of the present invention requires only one molar equivalent of the expensive indole starting material. This contrasts with the two equivalents required by the prior art process and effectively doubles the yield of acylated material based on indole starting material.
According to the present invention, there is provided a method for the preparation of 3-acylated indoles which involves preparing the acid chloride as described and then adding solutions of (i) the acid chloride and (ii) an alkyl or aryl magnesium halide separately and simultaneously to a stirred solution of the indole in such a way that (a) the two streams of incoming reagents do not come into immediate contact, i.e. they are added some distance apart to prevent their reacting with one another rather than with the indole, and (b) the two reagents are added at xe2x80x98synchronisedxe2x80x99 rates of molar addition.
Specifically, the invention provides a process for the preparation of a compound of formula (I) 
wherein R=C1-C6 alkyl, C1-C6 alkoxy, C3-C7 cycloalkyl, aryl optionally substituted by one or more of hydroxy, C1-C4 alkyl, C1-C4 alkoxy, fluoro, fluoro(C1-C4)alkyl and fluoro(C1-C4)alkoxy, or N-carboxybenzyl-2-pyrrolidinyl and X is hydrogen or one or more substituents independently selected from cyano, halogen, nitro, C1-C6 alkyl, C1-C6 alkoxy, C3-C7 cycloalkyl and aryl optionally substituted by one or more of cyano, halogen, nitro, C1-C4 alkyl, C1-C4 alkoxy, fluoro(C1-C4)alkyl and fluoro(C1-C4)alkoxy;
which comprises separately and simultaneously adding to a stirred solution of an indole of formula (II) 
wherein X is as hereinbefore defined;
(i) a solution containing an acid chloride of formula RCOCl wherein R is as hereinbefore defined; and
(ii) a solution containing an alkyl or aryl magnesium halide in such a way that
(a) the solutions (i) and (ii) are added with sufficient separation to prevent their reacting with one another; and
(b) the solutions (i) and (ii) are added at equivalent rates of molar addition.
According to particularly preferred features of the invention, the indole of formula (II) is indole itself or a 5-haloindole and the magnesium halide is an alkyl or aryl magnesium bromide, preferably ethyl magnesium bromide.